tbuckley/cabot-search huggingface dataset:
Abstract 2006: Preclinical evaluation of dual AURKA (LY3295668) and BCL2 (venetoclax) inhibition in neuroblastoma (NB)
Authors: David Groff, Colleen Casey, Kateryna krytska, Matthew Tsang, Christina Acholla, John M. Maris, Yael P. Mosse
Journal: Cancer Research (2022)

Abstract Introduction: Deregulated expression of the MYCN oncogene is associated with the development of many neural-derived pediatric cancers including NB, medulloblastoma and atypical teratoid rhabdoid tumors. Amplification of the MYCN oncogene is present in over 40% of high-risk NBs that remain lethal in most patients, thus developing better therapies for these patients is essential. While direct therapeutic targeting of MYCN protein remains challenging, we previously demonstrated synergistic activity of dual targeting of BCL-2 (venetoclax) and AURKA (MLN8237) in MYCN-amplified NB (Ham Cancer Cell, 2016). With MLN8237 no longer being developed due to toxicities related to AURKB inhibition, testing of a highly selective AURKA inhibitor, LY3295668, is warranted. Methods: LY3295668 (Chemie Tek) and venetoclax (Selleck Chem) were tested alone and in combination in six NB PDX models using 2-3 mice/arm. Five Patient Derived Xenograft (PDX) models tested (COG-N-424x, COG-N-453x, NB-1643, Obelix-Rx and Obelix-2x) were MYCN-amplified and one xenograft model (SK-N-AS) was MYCN-non-amplified. First, a comprehensive toxicity study, testing LY3295668 at 30mg/kg with venetoclax at 100mg/kg, 75mg/kg, 50mg/kg, and 25mkg/kg, was performed. Based on tolerability of combination, an optimal dose of 30mg/kg for LY3295668 and 50mg/kg for venetoclax was selected and administered once daily, seven days a week, via oral gavage for 60 days. These were the maximum tolerated doses when tested in combination, that did not result in weight loss greater than 15% or other overt signs of toxicity. Results: LY3295668 (30mg/kg) and venetoclax (50mg/kg) were well tolerated as monotherapy, and when administered in combination showed a maximum weight loss of 13%. Single agent therapy resulted in minimal if any growth delay. Four of five MYCN-amplified PDX models demonstrated maintained complete responses and one showed significant tumor growth delay. No effect was observed in the MYCN-non-amplified model with single agent or combination treatment compared to vehicle. Conclusions: Dual targeting of AURKA and BCL2 with LY3295668 and venetoclax is tolerable and demonstrates compelling anti-tumor activity in MYCN-amplified NB PDX models, validating our earlier findings (Ham et al). These preclinical results provisionally support clinical development of this combination for NB patients with MYCN amplification. Assessment of additional PDX models is currently ongoing and will be reported. Citation Format: David Groff, Colleen Casey, Kateryna krytska, Matthew Tsang, Christina Acholla, John M. Maris, Yael P. Mosse. Preclinical evaluation of dual AURKA (LY3295668) and BCL2 (venetoclax) inhibition in neuroblastoma (NB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2006.
Abstract 5664: Characterization of OASEP1 as a biomarker and therapeutic target for oral cancer
Authors: Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yataro Daigo
Journal: Cancer Research (2022)

Abstract This study aims to identify new biomarkers and therapeutic targets for oral cancer. Our strategies are as follows: i) Identification of overexpressed genes in oral cancers by gene expression array analysis, ii) Validation of clinicopathologic significance of their protein expression by tissue microarray, iii) Examination of their growth effect on cancer cell by siRNAs. We identified a secreted protein, OASEP1 (oral cancer-associated serum protein 1) as a candidate. Immunohistochemical staining showed that OASEP1 protein expression was observed in 120 (75.4%) of 159 oral cancers that had undergone curative surgery. High level of OASEP1 expression was associated with poor prognosis for oral cancer patients (P = 0.0054, by log-rank test). Multivariate analysis revealed that strong OASEP1 expression was an independent prognostic factor. Suppression of OASEP1 expression by siRNA specific for OASEP1 significantly inhibited the growth of oral cancer cell lines through apoptosis as detected by apoptosis assays and time lapse imaging. In addition, siRNAs for the receptor of OASEP1 also significantly inhibited the growth of oral cancer cells. Enforced OASEP1 expression significantly enhanced the growth of cancer cells. Addition of OASEP1 protein significantly increased the growth of oral cancer cells in a dose dependent manner, suggesting that the interaction between OASEP1 and its receptor regulated the growth of oral cancer cells. Microarray analysis coupled with siRNAs for OASEP1 demonstrated various OASEP1-related oncogenic pathways in oral cancer cells. Our data suggest that OASEP1 is a possible prognostic biomarker and therapeutic target for oral cancer. Citation Format: Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yataro Daigo. Characterization of OASEP1 as a biomarker and therapeutic target for oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5664.
Abstract 3430: CD47 x ICAM-1 bispecific antibody represents a novel approach for treating ICAM-1 overexpressing tumors
Authors: Xinhua Wang, Oi Kwan Wong, Leonard Post, Xiaocheng Chen
Journal: Cancer Research (2022)

Abstract CD47/SIRPa axis is an important checkpoint of innate immune system, CD47 interacts with its ligand signal regulatory protein-alpha (SIRPa) on myeloid cells, conveys a “don’t eat me” signal and blocks macrophage mediated phagocytosis. Tumor cells, which express high level of CD47, exploit this mechanism to evade from immune surveillance. CD47 is considered a prominent target for cancer treatment. However, the wide expression of CD47 on normal cells could cause antigen sink and lead to safety issues, such as anemia and thrombocytopenia. ICAM-1 is constitutively present at low levels on endothelial cells, but its overexpression has been observed on various types of tumors, such as primary myeloma, lymphoma and kidney cancer. Here we describe a novel CD47 x ICAM-1 bispecific antibody, which specifically targets CD47+/ICAM-1+ tumors in preclinical studies.A novel anti-CD47 antibody and an anti-ICAM-1 antibody were used for the generation of a CD47 x ICAM-1 bispecific antibody. In vitro assays including FACS binding, FACS-based SIRPa blocking, ADCP, RBC binding and hemagglutination were performed to characterize the bispecific CD47 x ICAM-1 antibody. In vivo efficacies of CD47 x ICAM-1 bispecific antibody were evaluated in xenograft tumor models with high ICAM-1 expression.The CD47 x ICAM-1 bispecific antibody selectively exhibited potent SIRPa blocking and antibody-dependent cellular phagocytosis (ADCP) activity on CD47+/ICAM-1+ tumor cells, but not on cells lacking ICAM-1 expression. Minimal RBC binding and RBC phagocytosis were observed upon treatment with CD47 x ICAM-1 bispecific antibody. The bispecific antibody did not cause any appreciable hemagglutination with up to 1µM antibody treatment. Most importantly, the CD47 x ICAM-1 bispecific antibody demonstrated potent anti-tumor activities in in vivo CDX and PDX models that overexpress both CD47 and ICAM-1. Our findings suggest that the novel CD47 x ICAM-1 bispecific antibody selectively binds to CD47 and blocks CD47/SIRPa binding on ICAM1 overexpressing tumor cells. The bispecific antibody has minimal RBC binding compared to the bivalent CD47 monoclonal antibodies and benchmark anti-CD47 antibodies. The bispecific antibody shows potent in vivo efficacy and specificity toward ICAM-1+/CD47+ positive tumor cells and represents a novel approach for treating ICAM-1+/CD47+ tumors. Citation Format: Xinhua Wang, Oi Kwan Wong, Leonard Post, Xiaocheng Chen. CD47 x ICAM-1 bispecific antibody represents a novel approach for treating ICAM-1 overexpressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3430.
Abstract 5097: Influencing factors of postoperative prognosis and screening of adjuvant chemotherapy in patients with early NSCLC
Authors: Xiaoning Li, Haibo Tang, Jianhong Cai, Xiaomin Wu, Xue Hu, Yating Zheng, Mengli Huang
Journal: Cancer Research (2022)

Abstract Introduction: The standard treatment for patients with stage I non-small cell lung cancer (NSCLC) is resection of the primary tumor. However, more than 28% of patients had recurrence or metastasis after surgery. Different studies have shown that the prognosis of stage I NSCLC is significantly different, due to the paucity of evidence for these adjuvant treatments after surgery, whether or not to apply adjuvant chemotherapy is controversial. In conclusion, postoperative adjuvant chemotherapy may be necessary for high-risk groups. Nevertheless, for patients with stage I NSCLC, the factors influencing the postoperative prognosis remains unclear. Methods: Data from LUAD and LUSC cohorts of The Cancer Genome Atlas (TCGA) was used to analyze the disease-free survival (DFS), overall survival (OS), progression-free survival (PFS) and cancer-specific survival (CSS) of different signaling pathways. DFS and OS Kaplan-Meier curves for subgroups of patients were compared using the log-rank test. Cox proportional hazards regression analysis was utilized to identify the independent predictors of DFS. Results: 270 LUAD and 234 LUSC of stage I patients were used in the analysis, through 16 variables, including age, sex, and 14 different signaling pathways associated with tumor development. For the LUAD patients, HR of DFS of notch signaling group is 1.89 (95%CI: 1.03-3.48, P=0.04) in univariate analysis, 2.73 (95%CI: 1.18-6.32, P=0.02) in multivariate analysis; HR of DFS of angiogenesis group is 2.30 (95%CI: 1.26-4.18, P=0.006) in univariate analysis, 2.65 (95%CI: 1.31-5.34, P=0.007) in multivariate analysis. HR of PFS of p53 group is 1.72 (95%CI: 1.08-2.73, P=0.023) in univariate analysis. Others are negatively correlated or have no significant differences. For the LUSC, all the factors are negatively correlated or have no significant differences. Conclusions: These results suggest that harboring notch signaling pathway and angiogenesis pathway mutation may be the biomarker for adjuvant chemotherapy for the stage I LUAD patients, but further validation is needed in large clinical studies. Citation Format: Xiaoning Li, Haibo Tang, Jianhong Cai, Xiaomin Wu, Xue Hu, Yating Zheng, Mengli Huang. Influencing factors of postoperative prognosis and screening of adjuvant chemotherapy in patients with early NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5097.
Gut dysbiosis and the clinical spectrum in anti-Ro positive mothers of children with neonatal lupus
Authors: Robert M. Clancy, Miranda C. Marion, Hannah C. Ainsworth, Miao Chang, Timothy D. Howard, Peter M. Izmirly, Mala Masson, Jill P. Buyon, Carl D. Langefeld
Journal: Gut Microbes (2022)

Anti-SSA/Ro antibodies, while strongly linked to fetal cardiac injury and neonatal rash, can associate with a spectrum of disease in the mother, ranging from completely asymptomatic to overt Systemic Lupus Erythematosus (SLE) or Sjögren's Syndrome (SS). This study was initiated to test the hypothesis that the microbiome, influenced in part by genetics, contributes to disease state. The stool microbiome of healthy controls (HC) was compared to that of anti-SSA/Ro positive women whose children had neonatal lupus. At the time of sampling, these women were either asymptomatic (Asym), had minor rheumatic symptoms or signs considered as an undifferentiated autoimmune syndrome (UAS), or were diagnosed with SLE or SS. Differences in microbial relative abundances among these three groups were tested assuming an ordering in clinical severity (HC<Asym/UAS<SS/SLE) and then again without the ordinal assumption. Those taxa that showed differential relative abundances were then tested for whether the effect size differed depending on the women's HLA SLE-risk allele genotype (DRB1*03:01, DRB1*15:01, DQB1*02:01 and DQB1*06:02) or anti-SSA/Ro autoantibody levels. Multiple genera within the families Ruminococcaceae and Lachnospiraceae showed evidence of an HLA-by-genus interaction (P < .05). Four genera exhibited evidence of an interaction with anti-Ro52 IgA: Lachnoclostridium, Romboutsia, Bacteroides and Actinomyces (P < .01). In addition to documenting differences in microbial relative abundances across clinical severity of disease, these data provide a first-time demonstration that microbial differences are correlated with HLA SLE-risk alleles. Taken together, these data suggest that the clinical spectrum from benign to overt clinical autoimmunity may partially result from or trigger a complex interplay among specific microbial profiles, anti-Ro autoantibodies, and genetics.
Abstract LB568: Protein phosphatase 4 deficiency protects mice against cerulein-induced acute pancreatitis
Authors: Hua Wang, Reza Abbasgholizadeh, Rohan Moniruzzaman, Baoan Ji, Anirban Maitra, Huamin Wang
Journal: Cancer Research (2022)

Abstract Background: Pancreatitis is an inflammatory disease of the pancreas that causes significant morbidity and mortality and is one of the major risk factors for pancreatic cancer. Protein phosphatase 4 (PP4) has been reported to be overexpressed in breast, lung and pancreatic cancers. PP4 plays an important role in the regulation of centrosome maturation, DNA repair, NF-κB, and c-jun-NH2-kinase (JNK) signaling pathways. However, the expression and functions of PP4 in pancreatitis have not been studied. Methods: To examine the functions of PP4 in cerulein-induced acute pancreatitis (AP), we crossed PP4flox/+ mice with pancreatic acinar cell specific cre, CreERT, which was driven by a full length pancreatic acinar specific elastase I promoter. PP4flox/flox, CreERT mice and control mice were treated with 8 hourly intraperitoneal injections of cerulein (50 µg/kg/h). The pancreata were harvested at different time points for histopathological examination and molecular analysis. Results: PP4 expression was increased at both protein and mRNA levels in mouse pancreas with AP. Compared to CreERT mice, PP4flox/flox, CreERT mice demonstrated significantly less edema, less inflammation, less necrosis or loss of pancreatic acinar cells in pancreas after cerulein treatment. The serum amylase and lipase levels were lower in cerulein-treated PP4flox/flox, CreERT mice compared with controls. The pancreata of PP4flox/flox, CreERT mice exhibited decreased STAT3 Tyr705 phosphorylation and decreased NF-κB activation cerulein-treated PP4flox/flox, CreERT mice than control mice. Conclusion: Our findings demonstrated that PP4 plays an important role in cerulein-induced AP through STAT3 and NF-κB signaling pathways. Inhibition of PP4 may help to reduce the pancreatic injuries and to prevent the development of chronic pancreatitis, which increases the risk of pancreatic cancer. Citation Format: Hua Wang, Reza Abbasgholizadeh, Rohan Moniruzzaman, Baoan Ji, Anirban Maitra, Huamin Wang. Protein phosphatase 4 deficiency protects mice against cerulein-induced acute pancreatitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB568.
Abstract 3622: DNA damage drives DNA methylation and 3D chromatin organization alterations in glioblastoma
Authors: Aram S. Modrek, Catherine Do, Zeyan Zhang, Yingwen Deng, Jerome Karp, Ravesanker Ezhilarasan, Giulia Cova, Matija Snuderl, Aristotelis Tsirigos, Jane Skok, Erik P. Sulman
Journal: Cancer Research (2022)

Abstract In glioblastoma, treatment with radiation and chemotherapy leads to DNA-damage and most DNA breaks are faithfully repaired, but the impact on the epigenome has not been thoroughly investigated. Since epigenetic alterations in DNA-methylation can impact the binding of factors involved in chromatin folding, such as CTCF as well as transcription factors that bind regulatory elements, the downstream impact on gene regulation could lead to the emergence of treatment resistance. Here, using radiation, we show there are significant and wide-spread alterations in DNA-methylation after treating multiple glioblastoma cultures. However, it is difficult to study these alterations because breaks are introduced at different sites in each cell, resulting in irreproducible DNA methylation alterations between replicates and cell lines. To circumvent this issue, we have developed a “multi-cut” CRISPR-Cas9 DNA break system that targets 142 or 483 pre-defined loci. We find that induction of mapped genome-wide cuts reproduces a similar level of toxicity as standard doses of radiation and we characterize the kinetics of overall cellular resolution of DNA damage using immunofluorescence markers and COMET assays. In order to assess repair efficiency (i.e., deletions, translocations, complete repair), we have designed a custom panel of DNA probes that flank the 142 or 483 sites to allow for high coverage sequencing of each cut site. To understand how DNA damage may lead to local epigenetic alterations and 3D chromatin organization changes, we performed HiC (genome-wide chromosome conformation capture), before and after cut induction, and subject cultures to further downstream analysis. Our findings show significant mega-base scale alterations in chromatin contacts centered around cut sites. To understand how these alterations may contribute to treatment resistance after DNA damage, we show these alternating chromatin contacts result in new promoter and enhancer interactions, which may drive gene-expression alterations after DNA damage at nearby loci. These results provide a mechanistic view of the interplay between DNA damage, DNA methylation and genome re-organization in glioblastoma. Importantly, these studies shed light on how these alterations evolve and their effect on local gene expression and ensuing treatment resistance. Citation Format: Aram S. Modrek, Catherine Do, Zeyan Zhang, Yingwen Deng, Jerome Karp, Ravesanker Ezhilarasan, Giulia Cova, Matija Snuderl, Aristotelis Tsirigos, Jane Skok, Erik P. Sulman. DNA damage drives DNA methylation and 3D chromatin organization alterations in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3622.
Abstract 4102: Vulnerability signature guided glioblastoma umbrella trial
Authors: Michael E. Berens, Sen Peng, Matthew Lee, Nanyun Tang, Manmeet S. Ahluwalia, Ekokobe Fonkem, Karen L. Fink, Jeffrey Raizer, Christopher Walker, Harshil Dhruv
Journal: Cancer Research (2022)

Abstract Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. A glioblastoma umbrella signature trial (GUST) posits multiple investigational treatment arms based on corresponding biomarker signatures. One contingency for an efficient umbrella trial is a suite of orthogonal signatures to classify patients into the likely most-beneficial arm. Assigning optimal thresholds of vulnerability signatures to classify patients as “most-likely responders” for each specific treatment arm is a crucial task. We utilized relative expression orderings (REO), entropy-regularized logistic regression (ERLR) and random forest classifier, to predict vulnerability classification. By applying semi-supervised algorithms to the TCGA GBM cohort, we were able to transform the samples with the highest certainty of predicted response into a self-labeled dataset and thus augment the training data. In this case, we developed a predictive model with a larger sample size and potentially better performance. Our GUST design currently includes four treatment arms for GBM patients: Arsenic Trioxide, Methoxyamine, Selinexor and Pevonedistat. Each treatment arm manifests its own signature developed by the customized machine learning pipelines based on selected gene mutation status, whole transcriptome data and real world outcomes from clinical trials. In order to increase the robustness and scalability, we also developed a multi-class/label classification ensemble model that’s capable of predicting a probability of “fitness” of each novel therapeutic agent for each patient. Such a multi-class model would also enable us to rank each arm and provide sequential treatment planning. By expansion to four independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients labeled 56% of all cases into at least one “high likelihood of response” arm. Predicted vulnerability using genomic data from preclinical PDX models correctly placed 4 out of 6 models into the “responder” group. Our utilization of multiple vulnerability signatures in a GUST trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM. Citation Format: Michael E. Berens, Sen Peng, Matthew Lee, Nanyun Tang, Manmeet S. Ahluwalia, Ekokobe Fonkem, Karen L. Fink, Jeffrey Raizer, Christopher Walker, Harshil Dhruv. Vulnerability signature guided glioblastoma umbrella trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4102.
Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials
Authors: Maija Dambrova, Marina Makrecka-Kuka, Janis Kuka, Reinis Vilskersts, Didi Nordberg, Misty M. Attwood, Stefan Smesny, Zumrut Duygu Sen, An Chi Guo, Eponine Oler, Siyang Tian, Jiamin Zheng, David S. Wishart, Edgars Liepinsh, Helgi B. Schiöth
Journal: Pharmacological Reviews (2022)

Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.